Multiple interacting genes and environmental factors determine the risk and trajectory of drug addiction. Expression of genes involved in the risk and consequences of addiction is influenced by environmental factors that in many cases are likely to leave persistent chemical modifications (epigenetic marks) in DNA and chromatin. We propose to comprehensively identify in archived postmortem human brain, changes in gene expression and linked epigenetic marks associated with chronic cocaine dependence. We will study two dopamine-dependent brain regions, the dorsal and ventral striatum. We will profile epigenetic marks in cocaine abusers with both short and long-term drug exposures. For analysis of the transcriptome, we will perform whole genome, strand- specific sequencing of mRNA transcripts (RNA-seq). For the DNA methylome, we will use MeDIP or equivalent technology to map the distribution of methyl CpG's at genome- wide and locus specific levels. The ultimate aim of this proposal is to discover which epigenetic changes in brain accompany the transition from cocaine abuse to chronic cocaine dependence. Discovery of cocaine-associated networks and pathways will provide clues to the etiology of cocaine addiction and will identify likely points of intervention in molecular and biochemical pathways that represent potential therapeutic targets. PUBLIC HEALTH RELEVANCE: Multiple interacting genes and environmental factors underlie the risk of drug addiction. First-time high throughput technologies will be used to develop epigenome maps of human brain, which are essential for understanding how epigenetic mechanisms figure in the neurobiology of drug abuse. We will profile epigenetic marks in human brain from chronic cocaine abusers to better our understanding and treatment of drug addiction.